Pyrrolylaminopiperidines

ABSTRACT

This invention relates to pyrrolylaminopiperidines and related compounds of the formula ##STR1## where R is hydrogen, loweralkyl, Arloweralkyl, cycloalkylloweralkyl, loweralkenyl and thienylloweralkyl; R 1  is lower alkyl, hydrogen, loweralkylcarbonyl, loweralkoxycarbonyl, loweralkylthiocarbonyl of the formula ##STR2## cyano, loweralkylaminocarbonyl, diloweralkylaminocarbonyl, cycloalkylcarbonyl, cycloalkylloweralkylcarbonyl and loweralkenylcarbonyl; R 2  is hydrogen, halogen and methyl; and the pharmaceutically acceptable acid addition salts thereof.

To the best of our knowledge the compounds of the present invention havenot heretofore been described or suggested.

The compounds of the present invention have the general formula ##STR3##where R is hydrogen, loweralkyl, Arloweralkyl, cycloalkylloweralkyl,loweralkanoyl and thienylloweralkyl; R₁ is hydrogen, loweralkyl,loweralkylcarbonyl, loweralkoxycarbonyl, loweralkylthiocarbonyl ##STR4##cyano, loweralkylaminocarbonyl, diloweralkylaminocarbonyl,cycloalkylcarbonyl, cycloalkylloweralkylcarbonyl andloweralkenylcarbonyl; R₂ is hydrogen, halogen and --CH₃ ; and thepharmaceutically acceptable salts thereof.

Particularly preferred compounds of the invention are those of CompoundI where R is phenylethyl; R₁ is loweralkoxycarbonyl, loweralkylcarbonyland cyano; and R₂ is hydrogen.

In the above definitions and as used hereinafter, the term "lower" meansthe group it is describing contains 1 to 6 carbon atoms. The term"alkyl" refers to a straight or branched chain hydrocarbon containing nounsaturation, e.g. methyl, ethyl, propyl, tertiary-butyl, isopropyl,etc. The term "Arloweralkyl" refers to a monovalent substitutent whichconsists of an aryl group, e.g. phenyl, p-nitrophenyl, o-toluyl,m-methoxyphenyl, etc., linked through a lower alkylene group having itsfree valence bond from a carbon of the lower alkylene group and having aformula of ##STR5## where Z is hydrogen, halogen, CF₃, NO₂, NH₂,loweralkyl, and loweralkoxy. The term "alkylene" refers to a bivalentradical of the lower branched or unbranched alkyl group it is derivedfrom having valence bonds from two terminal carbons thereof, e.g.,ethylene (--CH₂ CH₂ --), propylene (--CH₂ CH₂ CH₂ --), isopropylene##STR6## etc. The term "alkoxy" refers to a monovalent substituent whichconsists of an alkyl group linked through an ether oxygen having itsfree valence bond from the ether oxygen, e.g. methoxy, ethoxy,isopropoxy, butoxy, etc. The term "halogen" refers to a member of thefamily consisting of fluorine, chlorine, bromine and iodine. The term"cycloalkylloweralkyl" refers to a monovalent substituent consisting ofa saturated hydrocarbon group possessing at least one carbocyclic ringof 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, etc., linked through a lower alkyl group. Theterm "alkenyl" refers to a straight or branched chain hydrocarboncontaining one unsaturated or double bond, e.g. ##STR7## etc. The term"thienylloweralkyl" means ##STR8##

The compounds of the present invention are prepared in the followingmanner. The substituents R, R₁ and R₂ are as defined above unlessindicated otherwise.

A substituted 1-aminopyrrole of the formula ##STR9## is selected.Compound II is typically prepared in the manner described in Flitsch etal., Chem. Ber. 102, 3268-3276 (1969) which describes the preparation of1-aminopyrrole and substituted 1-aminopyrroles.

Compound II is condensed with Compound III having the formula ##STR10##by heating at 80° to 120° C. for 2 to 24 hours in the presence of aninert solvent, e.g. benzene, toluene, cyclohexane, etc., followed byreduction with an agent such as sodium borohydride in a solvent such asisopropanol at 60°-80° to form a condensation product of the inventionhaving the formula ##STR11##

Compound IV is reacted under conventional substitution reactionconditions, typically in the presence of a polar solvent, e.g.dimethylformamide, dichloromethane, chloroform, etc. a base, such as forexample K₂ CO₃, Na₂ CO₃, NaHCO₃, etc., at a temperature of 25° to 60° C.for 2 to 24 hours, with an acid halide having the formula ##STR12##where Hal is a halogen and R₃ is lower alkyl of 1 to 5 carbon atoms [(C₁-C₅)-alkyl], cycloalkyl and loweralkenyl of 1 to 5 carbon atoms [(C₁-C₅)-alkenyl] to form a compound of the invention having a formula##STR13## The carbonyl group of compound V in turn can be reduced in aconventional manner, e.g. with borane-tetrahydrofuran complex at atemperature of -30° C. to 0° C. for a time of 1 minute to 60 minutes,with zinc amalgam in hydrochloric acid, hydrogen in the presence of acatalyst, such as Pd, etc., to provide Compound I, where R₁ isloweralkyl of 1 to 6 carbon atoms, when R₃ is (C₁ -C₅) alkyl or (C₁ -C₅)alkenyl; or to provide Compound I where R₁ is loweralkylcycloalkyl whenR₃ is cycloalkyl. Compound V, where R₃ is (C₁ -C₅) alkyl, is reacted inthe manner reported in Bull. Soc. Chim. Belg. 87, (3), 229-238 (1978)with p-methoxyphenylthionophosphine sulfide dimer to form a compound ofthe invention having the formula ##STR14##

Compound IV is reacted under conventional substitution reactionconditions with a halocyanide of the formula Hal--CN, where Hal is ahalogen, e.g. Br, to form a compound of the invention having the formula##STR15## Typically the reaction is carried out in a polar solvent, e.g.dimethylformamide, chloroform, dichloromethane, etc. at a temperature of25° to 60° C. for 2 to 24 hours.

Compound IV is reacted, under conventional substitution reactionconditions, in a polar solvent at 25° to 60° C. for 2 to 24 hours with ahaloformate ester of the formula ##STR16## where Hal is a halogen and R₄is a (C₁ -C₆) alkyl to form a compound of the invention having theformula ##STR17##

Compound IV is reacted with an isocyanate compound of the formula R₅--N═C═O (X) where R₅ is (C₁ -C₆) alkyl to form a compound of theinvention having the formula ##STR18## Typically this reaction iscarried out in a nonpolar solvent, e.g. benzene, toluene, xylene, etc.,at a temperature of 50° to 80° C. for 4 to 24 hours. Compound XI in turncan be further N-substituted in a conventional manner of alkylation,such as for example by treatment of the sodium salt thereof (from sodiummetal or sodium hydride) with an alkyl iodide, e.g. methyliodide, ordimethylsulfate.

Compounds of the present invention are useful as analgesic agents due totheir ability to alleviate pain in mammals. The activity of thecompounds is demonstrated in the 2-phenyl-1,4-benzoquinone-inducedwrithing test in mice, a standard assay for analgesia [Proc. Soc. Exptl.Biol. Med. 95, 729 (1957)].

The analgesic activity of some of the compounds expressed in a dosage ofthe compounds which exhibit either (a) a 50% effective dose inhibition(ED₅₀) or (b) a percent inhibition is given in Table I.

                  TABLE I                                                         ______________________________________                                                       (ED.sub.50)                                                                   Subcuta- (ED.sub.50)    Sub-                                                  neous    Oral           cuta-                                                 Dose in  Dose           neous                                                 Mg/kg of in Mg/kg %     Dose                                                  Body     of Body  (De-  (Mg/                                   Compound       Weight   Weight   crease)                                                                             kg)                                    ______________________________________                                        N--[1-(2-phenethyl)                                                                          .0..35   1.4      --    --                                     piperidin-4-yl]-                                                              N--(1H--pyrrol-1-yl)                                                          propanamide                                                                   hydrochloride                                                                 N--[1-(2-phenethyl)                                                                          1.2      9.5      --    --                                     piperidin-4-yl)]-                                                             N--(1H-pyrrol-1-yl)-                                                          acetamide                                                                     hydrochloride                                                                 N--[1-(2-phenethyl)                                                                          2.4      5.6      --    --                                     piperidin-4-yl]-                                                              N--(1H--pyrrol-1-yl)                                                          carbamic acid                                                                 ethyl ester                                                                   hydrochloride                                                                 N--[1-(2-phenethyl)                                                                          .0..65   7.7      --    --                                     piperidin-4-yl]-N--                                                           (1H--pyrrol-1-yl)                                                             carbamic acid methyl                                                          ester hydrochloride                                                           N--[1-(2-phenethyl)                                                                          2.4      --       --    --                                     piperidin-4-yl]-                                                              N--(1H--pyrrol-1-yl)                                                          cyanamide                                                                     hydrochloride                                                                 N--{1-[2-(4-   --       --       76    4.0.                                   chlorophenyl)ethyl]                                                           piperidin-4-yl}-N--                                                           (1H--pyrrol-1-yl)                                                             propanamide                                                                   N--[1-(n-butyl)                                                                              --       --       2.0.  2.0.                                   piperidin-4-yl]-N--                                                           (1H--pyrrol-1-yl)                                                             carbamic acid ethyl                                                           ester                                                                         N--[1-(n-butyl)                                                                              --       --       45    1.0.                                   piperidin-4-yl]-                                                              N--(1H--pyrrol-1-yl)                                                          propanamide                                                                   maleate                                                                       1-(2-phenethyl)-                                                                             --       --       49    1.0.                                   4-(1H--pyrrol-1-yl)                                                           aminopiperidine                                                               maleate                                                                       N--{1-[2-(4-methoxy-                                                                         --       --       27    1.0.                                   phenyl)ethyl]piperidin-                                                       4-yl}-N--(1H--pyrrol-                                                         1-yl)propanamide                                                              N--{1-[2-(4-methoxy-                                                                         --       --       51    1.0.                                   phenyl)ethyl]piperidin-                                                       4-yl}-N--(1H--pyrrol-                                                         l-yl)cyanamide                                                                hydrochloride                                                                 1-(2-phenethyl)-4-                                                                           --       --       53    1.0.                                   [N--(n-propyl)-N--(1H--                                                       pyrrol-1-yl)]amino-                                                           piperidine oxalate                                                            N--[1-(2-phenyl-                                                                             --       --       3.0.  1.0.                                   propyl)-piperidin-                                                            4-yl]-N--(1H--pyrrol-                                                         l-yl)propanamide                                                              hydrochloride                                                                 N--[1-(2-phenyl-                                                                             --       --       42    1.0.                                   propyl)piperidin-4-                                                           yl]-N--(1H--pyrrol-1-                                                         yl)carbamic acid                                                              ethyl ester                                                                   N--[1-(2-phenethyl)                                                                          --       --       1.0..0.                                                                             1.0.                                   piperidin-4-yl]-N--                                                           (1H--pyrrol-1-yl)                                                             acrylamide                                                                    hydrochloride                                                                 N--[1-(2-phenethyl)                                                                          --       --       1.0..0.                                                                             1.0.                                   piperidin-4-yl]-N--                                                           (1H--pyrrol-1-yl)-N'--                                                        methylurea                                                                    hydrochloride                                                                 N--[1-(2-phenethyl)                                                                          --       --       65    1.0.                                   piperidin-4-yl]-N--                                                           (1H--pyrrol-1-yl)                                                             cyclobutanecarboxylic                                                         acid amide                                                                    hydrochloride                                                                 N--{1-[2-(2-thienyl)                                                                         --       --       54    1.0.                                   ethyl]piperidin-4-                                                            yl}-N--(1H--pyrrol-1-                                                         yl)carbamic acid                                                              ethyl ester                                                                   hydrochloride                                                                 N--[1-(2-phenethyl)                                                                          --       --       99    1.0.                                   piperidin-4-yl]-                                                              N--(1H--pyrrol-1-yl)                                                          propanethioamide                                                              hydrochloride                                                                 ______________________________________                                    

Effective amounts of the compounds of the present invention may beadministered to a subject by one of various methods, for example, orallyas in capsules or tablets, parenterally in the form of sterile solutionsor suspensions, and in some cases intravenously in the form of sterilesolutions. The compounds of the invention, while effective themselves,may be formulated and administered in the form of their pharmaceuticallyacceptable acid addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable acid addition salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, nitric, phosphoric, perchloric acids and the like as well asorganic acids such as tartaric, citric, succinic, maleic, fumaric acidsand the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the pyrrolylaminopiperidinesand related compounds of the invention, the active ingredient, but maybe varied depending upon the particular form and may conveniently bebetween 4% to about 70% of the weight of the unit. The amount of thecompound present in such compositions is such that a suitable dosagewill be obtained. Preferred compositions and preparations according tothe present invention are prepared so that an oral dosage unit formcontains between 5.0-300 milligrams of the pyrrolylaminopiperidines andrelated compounds of the invention.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added to a flavoring agent such as peppermint, methylsalicylate or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to material of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the present compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of thepyrrolylaminopiperidines and related compounds of the invention, but maybe varied to be between 0.1 and about 50% of the weight thereof. Theamount of the inventive compound present in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 5.0 to 100 milligrams of thepyrrolylaminopiperidine and related compounds of the invention.

The solutions or suspensions may also include the following adjuvants: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylene diaminetetraacetic acid, buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following examples are for illustrative purposes and are not to beconstrued as limiting the invention disclosed herein. All temperaturesare given in degrees centigrade unless indicated otherwise.

EXAMPLE 1 N-(1-Methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamidemaleate

A solution of 1-aminopyrrole (4.2 g, 0.05 mol) and 1-methyl-4-piperidine(6.9 g, 0.06 mol) in cyclohexane was refluxed overnight (about 16 hours)over 4 Å molecular sieves. After 3 hours, an additional 1 g of1-methyl-4-piperidone was added. The molecular sieves were filtered offand the cyclohexane removed by evaporation under reduced pressure. Theresulting oil was dissolved in isopropanol and 5 g of sodium borohydrideadded. The mixture was stirred at reflux for three hours, then methanolwas added, the heat was removed, and stirring continued until themixture had cooled to room temperature. The solvent was removed byevaporation under reduced pressure to give a residue to which water wasadded. This mixture was extracted with dichloromethane, thedichloromethane solution was dried with saturated sodium chloridesolution and magnesium sulfate, and the dichloromethane evaporated invacuo to give 7 g (78%) of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine.To a cooled solution of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine (5.4g, 0.03 mol) and triethylamine (3.35 g, 0.033 mol) in CHCl₃ (100 ml) wasadded dropwise a solution of propionyl chloride (3.07 g, 0.033 mol) inCHCl₃ (100 ml). The reaction mixture was stirred at ice bath temperaturefor one hour, then at room temperature overnight (about 16 hours). Thechloroform solution was washed with water, dried with saturated sodiumchloride and magnesium sulfate, and the chloroform removed to give 4.8 gof an oil. The oxalate was formed by adding ethereal oxalic acid but didnot crystallize. The resultant oil was basified, extracted withdichloromethane and dried to give 3.2 g of an oil. This oil waschromatographed on a high pressure liquid chromatograph (HPLC) using11/2% diethylamine in acetonitrile. The resultant 1.5 g of free base wasconverted to the maleate (1.9 g) by adding ethereal maleic acid andrecrystallized from absolute ethanol/ether to give 1.8 g, m.p. 146°-147°C. of N-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate.The recovered starting material was reacted again with propionylchloride (0.7 g) in CH₂ Cl₂ (20 ml) with sodium bicarbonate (1 g) atroom temperature overnight. Work-up gave an oil which was dissolved inether, and an ether solution of maleic acid added to give the maleatesalt. Recrystallization from absolute ethanol/ether gave an additional1.5 g of product ofN-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate, mp146°-147° C., combined yield 3.3 g (9.39 mmol), 31.3% yield from1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine.

ANALYSIS: Calculated for C₁₃ H₂₁ N₃ O.C₄ H₄ O₄ : 58.09%C; 7.18%H;11.96%N. Found: 58.29%C; 7.02%H; 12.05%N.

EXAMPLE 2N-[1-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamidehydrochloride

A solution of 1-aminopyrrole (6 g, 73 mmole) and1-(2-phenethyl)-4-piperidone (16 g, 80 mmole) in 250 ml benzene wasstirred six hours at reflux. The reaction mixture was cooled, filteredand evaporated to 20 g of an oil. This oil was dissolved in 200 mlisopropanol and 50 ml methanol and stirred two hours at reflux withNaBH₄ (6 g, 0.16 mole). The reaction mixture was cooled and evaporatedto a semi-solid which was stirred with water and extracted with ether.The organic extract was washed with water, saturated NaCl and was dried(anhydrous MgSO₄), filtered and evaporated to 20 g of an oil. This oilwas purified by HPLC to give 17 g (86%) of an oil comprising1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine. To a solution of1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine (4.5 g, 17 mmole) in150 ml dichloromethane containing sodium bicarbonate (2.8 g, 33 mmole)was added a solution of propionyl chloride (1.8 g, 10 mmole) in 10 mldichloromethane. After stirring two days at ambient temperature, thereaction mixture was evaporated to an oil that was stirred with waterand extracted with ethyl acetate. The organic extract was washed withwater and saturated NaCl and was dried (anhydrous MgSO₄), filtered andevaporated to 5.4 g of an oil. This oil was converted to thehydrochloride salt by adding ethereal hydrogen chloride andrecrystallized from isopropanol/methanol to give 5.1 g (84%) ofN-[1-(2-phenethyl)-piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamidehydrochloride, d 270° C.

ANALYSIS: Calculated for C₂₀ H₂₇ N₃ O.HCl: 66.37%C; 7.80%H; 11.61%N.Found: 66.53%C; 7.80%H; 11.58%N.

EXAMPLE 3 N-[1-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)acetamidehydrochloride

To a solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11 (4.5 g, 17 mmole) in 200 ml dichloromethane containing sodiumbicarbonate (2.8 g, 33 mmole) was added a solution of acetyl chloride(1.5 g, 19 mmole) in 20 ml dichloromethane. After stirring twenty hoursat ambient temperature, the mixture was evaporated to a solid that wasstirred with water and extracted with ethyl acetate-ether. The organicextract was washed with water and saturated NaCl and was dried(anhydrous MgSO₄), filtered and evaporated to 5.4 g of a solid. Thismaterial was converted to the hydrochloride as in Example 2 andrecrystallized from isopropanol-methanol to give 4.8 g (83%) ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)acetamidehydrochloride, d 278° C.

ANALYSIS: Calculated for C₁₉ H₂₅ N₃ O.HCl: 65.59%C; 7.53%H; 12.08%N.Found: 65.42%C; 7.48%H; 12.00%N.

EXAMPLE 4 N-[1-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamicacid ethyl ester hydrochloride

To a solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11 (4.1 g. 15 mmole) in 150 ml dichloromethane containing sodiumbicarbonate (2.6 g, 30 mmole) was added a solution of ethylchloroformate (1.9 g, 18 mmole) in 20 ml dichloromethane. After stirringtwenty hours at ambient temperature, the mixture was evaporated to asolid that was stirred with water and extracted with ethylacetate-ether. The organic extract was washed with water and saturatedNaCl and was dried (anhydrous MgSO₄), filtered and evaporated to 5.2 gof a solid. 3.5 g of the solid was converted to the hydrochloride saltas in Example 2 then recrystallized from isopropanol to give 2.6 g (67%)of N-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acidethyl ester hydrochloride.

ANALYSIS: Calculated for C₂₀ H₂₇ N₃ O₂.HCl 63.55%C; 7.47%H; 11.12%N.Found: 63.93%C; 7.58%H; 11.32%N.

EXAMPLE 5 N-[1-(2-Phenethyl)-piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamicacid methyl ester hydrochloride

To a solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11 (4 g, 15 mmole) in 150 ml dichloromethane containing sodiumbicarbonate (2.5 g, 30 mmole) was added a solution of methylchloroformate (1.6 g, 17 mmole) in 20 ml dichloromethane. After stirringtwenty hours at ambient temperature, the reaction mixture wasevaporated, stirred with water and extracted with ethyl acetate-ether.The organic extract was washed with water, saturated NaCl and was dried(anhydrous MgSO₄), filtered and evaporated to an oil (4.7 g) that waspurified by HPLC (silica gel, ethyl acetate/hexane/diethylamine-50/50/1)to give 3.7 g (76%) of a solid. This solid was converted to thehydrochloride salt as in Example 2 and recrystallized from isopropanolto give 3.6 g (67%) ofN-[1-(2-phenethyl)-piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acidmethyl ester hydrochloride, d 222°-223° C.

ANALYSIS: Calculated for C₁₉ H₂₅ N₃ O₂.HCl: 62.71%C; 7.20%H; 11.55%N.Found: 62.46%C; 7.35%H; 11.45%N.

EXAMPLE 6 N-[1-(2-Phenethyl)-piperidin-4-yl]-N-(1H-pyrrol-1-yl)cyanamidehydrochloride

To a solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11, (4 g, 15 mmole) in 150 ml dichloromethane containing 2.5 g(30 mmole) sodium bicarbonate was slowly added a solution of cyanogenbromide (1.8 g, 17 mmole) in 25 ml dichloromethane. After stirringtwenty hours at ambient temperature, the reaction mixture wasevaporated, stirred with water and extracted into ethyl acetate-ether.The organic extract was washed with water, saturated NaCl and was dried(anhydrous MgSO₄), filtered and evaporated to 5 g of an oil. This oilwas converted to the hydrochloride salt as in Example 2 andrecrystallized twice from isopropanol to give 2.7 g (55%) ofN-[1-(2-phenethyl)-piperidin-4-yl]-N-(1H-pyrrol-1-yl)cyanamidehydrochloride, d 211°-212° C.

ANALYSIS: Calculated for C₁₈ H₂₂ N₄.HCl: 65.34%C; 7.01%H; 16.94%N.Found: 65.04%C; 6.94%H; 17.06%N.

EXAMPLE 7

a. 1-[2-(4-chlorophenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine

A mixture of 1-[2-(4-chlorophenyl)ethyl]-4-piperidone (8 g, 33.6 mmole)and 1-aminopyrrole (2.7 g, 33.6 mmole) in 100 ml of benzene was stirredat reflux for 6 hours. An additional 0.5 g of 1-aminopyrrole was addedand reflux was continued for 2 hours whereafter an additional 0.5 g of1-aminopyrrole was added and refluxing was continued overnight (about 16hours). An additional 0.5 g of 1-aminopyrrole was added followed byrefluxing for 6 hours. The resultant mixture was evaporated to yield 13g of an oil. The oil was dissolved in 100 ml of isopropyl alcohol and 25ml of methanol. To the solution was added NaBH₄ (2.6 g, 68 mmole) andthe resultant mixture was refluxed for 2 hours. The mixture was cooled,evaporated with ethylacetate/ether. The organic extract was washed withwater, dried, filtered and evaporated to yield 12 g of an oil. The oilwas purified by high pressure liquid chromatography (silica, 1%ethanol/ethylacetate) to give 9.6 g (94%) of an oil of1-[2-(4-chlorophenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine whichsolidified at room temperature upon standing.

b.N-{1-[2-(4-Chlorophenyl)ethyl]-piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamicacidethyl ester hydrochloride

To a solution of1-[2-(4-chlorophenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine of Example7a, (3.6 g, 12 mmole) in 100 ml dichloromethane containing sodiumbicarbonate (2.5 g, 30 mmole) was added a solution of ethylchloroformate (1.6 g, 15 mmole) in 20 ml of dichloromethane. Thereaction mixture was stirred three hours at ambient temperature, thenwas evaporated, stirred with water and extracted with ethylacetate-ether. The organic extracts were washed with water, saturatedNaCl and were dried (anhydrous MgSO₄), filtered and evaporated to 4 g ofan oil. This oil was purified by HPLC (silica gel; dichloromethane/ethylacetate/diethylamine:100/20/1) to give 3.4 g of a solid. This materialwas converted to the hydrochloride salt as in Example 2 andrecrystallized from isopropanol to give 2.8 g (58%) ofN-{1-[2-(4-chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamicacid ethyl ester hydrochloride, d 253°-254° C.

ANALYSIS: Calculated for C₂₀ H₂₆ ClN₃ O₂.HCl: 58.25%C; 6.60%H; 10.19%N.Found: 58.44%C; 6.58%H; 10.28%N.

EXAMPLE 8N-{1-[2-(4-Chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamide

To a solution of1-[2-(4-chlorophenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine of Example7a, (5 g, 16 mmole) in 150 ml dichloromethane containing sodiumbicarbonate (3 g, 36 mmole) was added a solution of propionyl chloride(1.7 g, 18 mmole) in 20 ml dichloromethane. After stirring four hours atambient temperature, the reaction mixture was washed with water,saturated sodium chloride and was dried (anhydrous MgSO₄), filtered andevaporated to give 6 g of a solid. This material was purified by HPLC(silica gel, 20% ethyl acetate/dichloromethane) to give 3.6 g (61%) of asolid, mp 80°-85° C. This was recrystallized from isopropylether/petroleum ether (1:1) to give 2.5 g (42%) ofN-{1-[2-(4-chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamide,mp 85°-86° C.

ANALYSIS: Calculated for C₂₀ H₂₆ ClN₃ O: 66.74%C; 7.28%H; 11.68%N.Found: 66.54%C; 7.11%H; 12.00%N.

EXAMPLE 9

a. 1-(n-Butyl)-4-(1H-pyrrol-1-yl)aminopiperidine

A solution of 1-butyl-4-piperidone (6.2 g, 40 mmole) and 1-aminopyrrole(3.3 g, 40 mmole) in 100 ml of toluene was stirred at reflux overnight(about 16 hours). The mixture was cooled and then evaporated to an oil,which in turn was dissolved in 75 ml of isopropanol, and 22 ml ofethanol. To the solution was added NaBH₄ (3.8 g, 100 mmole). The mixturewas stirred at 70° C. for 2 hours and then evaporated, stirred withwater and extracted with ethyl acetate-ether. The organic extract waswashed with water and saturated NaCl solution, dried (anhydrous MgSO₄),filtered and evaporated to 13 g of an oil. This oil was purified by highpressure liquid chromatography (silica, 1% diethylamine/ethyl acetate)to give 8.2 g of an oil of1-(n-butyl)-4-(1H-pyrrol-1-yl)aminopiperidine.

b. N-[1-(n-Butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acid ethylester

To a solution of 1-(n-butyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 9a, (4 g, 18 mmole) in 100 ml dichloromethane containing sodiumbicarbonate (3 g, 36 mmole) was added a solution of ethyl chloroformate(2.3 g, 20 mmole) in 20 ml dichloromethane. After stirring three hoursat ambient temperature the reaction mixture was evaporated, stirred withwater and extracted with ethyl acetate. The organic extract was washedwith water and saturated NaCl and was dried (anhydrous MgSO₄), filteredand evaporated to give 4.8 g of an oil. This oil was purified by HPLC(silica gel, ethyl acetate) to give 3.3 g (62%) of an oil. This oil wasdistilled to give 2.3 g (43%) ofN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acid ethylester (b.p. 130°-140° C. @ 0.2 mm; m.p. 42°-43° C.).

ANALYSIS: Calculated for C₁₆ H₂₇ N₃ O₂ : 65.49%C; 9.28%H; 14.32%N.Found: 65.26%C; 9.04%H; 14.05%N.

EXAMPLE 10 N-[1-(n-Butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamidemaleate

To a solution of 1-(n-butyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 9a, (3.5 g, 16 mmole) in 150 ml dichloromethane containingsodium bicarbonate (4 g, 48 mmole) was added a solution of propionylchloride (1.6 g, 17 mmole) in 25 ml dichloromethane. After stirring fivehours at ambient temperature, the reaction mixture was evaporated,stirred with water and extracted with ether. The organic extract waswashed with water, saturated NaCl and was dried (anhydrous MgSO₄),filtered and evaporated to 4 g of an oil. This oil was purified by HPLC(silica, 20% ethyl acetate in dichloromethane) to give 3.4 g (78%) of anoil. This oil was converted to the maleate salt as in Example 1 andrecrystallized from isopropanol-ether to give 4 g (64%) ofN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)-propanamide maleate, mp131°-132° C.

ANALYSIS: Calculated for C₁₆ H₂₇ N₃ O.C₄ H₄ O₄ : 61.05%C; 7.94%H;10.68%N. Found: 61.14%C; 7.91%H; 10.66%N.

EXAMPLE 11 1-(2-Phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine maleate

A mixture of 1-(β-phenethyl)-4-piperidone (12.4 g, 61 mmole) and1-aminopyrrole (5 g, 61 mmole) in 100 ml benzene was stirred seven hoursat reflux. After cooling, the mixture was evaporated, dissolved in 100ml isopropanol and 25 ml methanol, and to this solution was added sodiumborohydride (4.6 g, 121 mmole). The mixture stirred two hours at 70° C.then was cooled, evaporated, stirred with water and extracted into ethylacetate-ether. The organic extract was washed with water, saturated NaCland was dried (anhydrous MgSO₄), filtered and evaporated to 17 g of anoil. This oil was purified by HPLC (silica, ethyl acetate) to give 14 g(85%) of a solid, mp 45°-47° C. Two grams of this material was convertedto the maleate salt as in Example 1 and recrystallized fromisopropanol-ether to give 2.5 g of1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine maleate, mp 147°- 148°C.

ANALYSIS: Calculated for C₁₇ H₂₃ N₃.C₄ H₄ O₄ : 65.43%C; 7.06%H; 10.90%N.Found: 65.29%C; 7.07%H; 10.88%N.

EXAMPLE 12

a. 1-[2-(4-Methoxyphenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine

A solution of 1-[2-(4-methoxyphenyl)ethyl-4-piperidone (15 g, 64 mmole)and 1-aminopyrrole (6 g, 73 mmole) in 125 ml of benzene was stirred at120° C. for 20 hours. The resultant solution was evaporated, dissolvedin 125 ml of isopropanol and 50 ml of methanol and then NaBH₄ (6 g, 158mmole) was added. The resultant mixture was stirred 3 hours at 75° C.,cooled, evaporated, stirred with water and then extracted with ethylacetate-ether. The organic extract was washed with water and saturatedNaCl solution, dried, (anhydrous MgSO₄), filtered and evaporated to 19.7g of an oil. This oil was purified by high pressure liquidchromatography (silica, 3% methanol/dichloromethane) to give 14.7 g(76.6%) of a solid. 0.5 g of this solid was recrystallized fromisopropyl ether to give 0.1 g of1-[2-(4-methoxyphenyl)ethyl]-4-(1H-pyrrol- 1-yl)aminopiperidine.

ANALYSIS: Calculated for C₁₈ H₂₅ N₃ O: 72.20%C; 8.42%H; 14.04%N. Found:72.51%C; 8.40%H; 14.10%N.

b.N-{1-[2-(4-Methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamide

To a solution of1-[2-(4-methoxyphenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 12a, (3.6 g, 12 mmole) in 100 ml dichloromethane containingsodium bicarbonate (2 g, 24 mmole) was added a solution of propionylchloride (1.1 g, 12 mmole) in 20 ml dichloromethane. After stirring twohours at ambient temperature, the reaction mixture was evaporated,stirred with water and extracted into ethyl acetate-ether. The organicextract was washed with water and saturated NaCl and was dried(anhydrous MgSO₄), filtered and evaporated to give 4 g of a solid. Thismaterial was recrystallized from isopropyl ether-petroleum ether (1:1)to give 2.8 g (65%) ofN-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamide,mp 83°-84° C.

ANALYSIS: Calculated for C₂₁ H₂₉ N₃ O₂ : 70.95%C; 8.22%H; 11.82%N.Found: 70.98%C; 8.24%H; 11.76%N.

EXAMPLE 13N-{1-[2-(4-Methoxyphenyl)ethyl]piperidin-4-yl})-N-(1H-pyrrol-1-yl)cyanamidehydrochloride

To a solution of1-[2-(4-methoxyphenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 12a (4 g, 13.4 mmole) in 150 ml dichloromethane containingsodium bicarbonate (3.4 g, 40 mmole) was added a solution of cyanogenbromide (1.6 g, 14.7 mmole) in 25 ml dichloromethane. After stirringtwenty hours at ambient temperature, the reaction mixture wasevaporated, stirred with water and extracted with ether. The organicextract was washed with water and saturated NaCl and was dried(anhydrous MgSO₄), filtered and evaporated to 5 g of an oil. The oil wasconverted to the hydrochloride salt as in Example 2 and wasrecrystallized from isopropanol-ether to give 2.8 g (58%)N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)cyanamidehydrochloride, d 227°-229° C.

ANALYSIS: Calculated for C₁₉ H₂₄ N₄ O.HCl: 63.23%C; 6.98%H; 15.53%N.Found: 63.17%C; 6.92%H; 15.42%N.

EXAMPLE 141-(2-Phenethyl)-4-[N-(n-propyl)-N-(1H-pyrrol-1-yl)]aminopiperidineoxalate

To a solution of borane-tetrahydrofuran (THF) complex (0.97 M in THF, 86mmole, 86 ml), cooled with an ice bath, was slowly added a solution ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamide ofExample 2, (7 g, 22 mmole) in 25 ml tetrahydrofuran. After stirringthree hours at ambient temperature the reaction mixture was cooled andexcess borane was quenched by slow addition of 3 N HCl. The mixture wasthen basified with sodium carbonate and the oil which separated wasextracted with ethyl acetate-ether. The organic extract was washed withwater and saturated NaCl and was dried (anhydrous MgSO₄), filtered andevaporated to give 8 g of a solid, mp 121°-123° C. A mixture of thissolid in 175 ml 3 N HCl was stirred three hours at 105° C., then wascooled, diluted with water and basified with sodium carbonate. The oilwhich separated was extracted with ethyl-acetate ether. The organicextract was washed with water, saturated NaCl and was dried (anhydrousMgSO₄), filtered and evaporated to give 7 g of an oil. This oil waspurified by HPLC (silica, ethyl acetate) to give 5 g (75%) of an oil.This oil was converted to the oxalate salt as in Example 1 and wasrecrystallized from isopropanol to give 5.5 g (64%) of1-(2-phenethyl)-4-[N-(n-propyl)-N-(1-H-pyrrol-1-yl)]aminopiperidineoxalate, d 188°-190° C.

ANALYSIS: Calculated for C₂₀ H₂₉ N₃.C₂ H₂ O₄ : 65.81%C; 7.78%H; 10.47%N.Found: 65.88%C; 7.71%H; 10.36%N.

EXAMPLE 15

a. 1-(2-Phenylpropyl)-4-(1H-pyrrol-1-yl)-aminopiperidine

A solution of 1-aminopyrrole (6 g, 73.1 mmole) and1-(2-phenylpropyl)-4-piperidone (13.8 g, 63.5 mmole) in 100 ml ofbenzene was stirred at reflux for 3 hours. The resultant mixture wasevaporated, dissolced in 100 ml of isopropanol and 25 ml of ethanol andto the resultant solution was added NaBH₄ (4.8 g, 0.13 mole). Theresultant mixture was stirred 2 hours at 70° C. and then kept at roomtemperature for 3 days. The mixture was evaporated, stirred with waterand extracted with ether. The organic extract was washed with water andsaturated NaCl solution and was dried (anhydrous MgSO₄), filtered andevaporated to 18 g of an oil. This oil was purified by high pressureliquid chromatography (silica, 3% methanol/dichloromethane) to give 14 g(77.8%) of an oil which on cooling yielded a solid of1-(2-phenylpropyl)-4-(1H-pyrrol-1-yl)aminopiperidine, m.p. 72°-74° C.

b. N-[1-(2-Phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamidehydrochloride

To a solution of 1-(2-phenylpropyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 15a, (3.5 g, 12.3 mmole) in 100 ml dichloromethane containingsodium bicarbonate (3.1 g, 37 mmole) was added a solution of propionylchloride (1.3 g, 13.6 mmole) in 20 ml dichloromethane. After stirringsix hours at ambient temperature the reaction mixture was evaporated,stirred with water and extracted into ether. The organic extract waswashed with water, saturated sodium chloride and was dried (anhydrousMgSO₄), filtered and evaporated to give 5 g of an oil. This oil wasconverted to the hydrochloride salt as in Example 2 and wasrecrystallized from isopropanol-ether to give 4.1 g (89%) ofN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamidehydrochloride, d 258°-259° C.

ANALYSIS: Calculated for C₂₁ H₂₉ N₃ O.HCl: 67.09%C; 8.04%H; 11.18%N.Found: 67.14%C; 7.98%H; 11.15%N.

EXAMPLE 16N-[1-(2-Phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acidethyl ester hydrochloride

To a solution of 1-(2-phenylpropyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 15a (3.5 g, 13.2 mmole) in 100 ml dichloromethane containingsodium bicarbonate (4 g, 48 mmole) was added a solution of ethylchloroformate (1.6 g, 15 mmole) in 20 ml dichloromethane. After stirringtwenty hours at ambient temperature, the reaction mixture wasevaporated, stirred with water and extracted into ether. The organicextract was washed with water, saturated NaCl and was dried (anhydrousMgSO₄), filtered and evaporated to give 4.5 g of an oil. The oil waspurified by HPLC (silica gel, ethyl acetate) to give 3.6 g (82%) of anoil. This oil was converted to the hydrochloride salt as in Example 2then recrystallized from isopropanol-ether to give 3.1 g (64%) ofN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acidethyl ester hydrochloride.

ANALYSIS: Calculated for C₂₁ H₂₉ N₃ O₂ HCl: 64.35%C; 7.72%H; 10.72%N.Found: 64.26%C; 7.76%H; 10.54%N.

EXAMPLE 17 N-[1-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamicacid-(n-butyl)-ester hydrochloride

To a solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11 (5 g, 10 mmole) in 150 ml dichloromethane containing sodiumbicarbonate (3 g, 36 mmole) was added a solution of butyl chloroformate(2.8 g, 20 mmole) in 20 ml dichloromethane. After stirring twenty hoursat ambient temperature, the reaction mixture was evaporated, stirredwith water and extracted with ether. The organic extract was washed withwater and saturated sodium chloride and was dried (anhydrous MgSO₄),filtered and evaporated to give 7 g of an oil. This oil was purified byHPLC (silica gel, 10% ethyl acetate in dichloromethane) to give 5.2 g(75%) of a solid mp 60° C. This material was converted to thehydrochloride salt as in Example 2 and was recrystallized fromisopropanol-ether to give 3.2 g (42%) ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamicacid-(n-butyl)-ester hydrochloride, d 216°-217° C.

ANALYSIS: Calculated for C₂₂ H₃₁ N₃ O₂.HCl: 65.09%C; 7.95%H; 10.35%N.Found: 65.37%C; 7.96%H; 10.38%N.

EXAMPLE 18N-[1-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)acrylamidehydrochloride

To a solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11 (4 g, 14.8 mmole) in 150 ml dichloromethane containing sodiumbicarbonate (4 g, 48 mmole) was added a solution of acryloyl chloride(1.5 g, 17 mmole) in 20 ml dichloromethane. After stirring twenty hoursat ambient temperature the reaction mixture was evaporated, stirred withwater and extracted with ethyl acetate-ether. The organic extract waswashed with water and saturated sodium chloride and was dried (anhydrousMgSO₄), filtered and evaporated to 4.8 g of a solid. This material waspurified by HPLC (silica gel, 20% ethyl acetate in dichloromethane) togive 3.3 g (69%) of a solid. This material was converted to thehydrochloride salt as in Example 2 and was recrystallized fromisopropanol to give 3.2 g (60%) ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)acrylamidehydrochloride, d 278°-279° C.

ANALYSIS: Calculated for C₂₀ H₂₅ N₃ O.HCl: 66.74%C; 7.28%H; 11.68%N.Found: 66.64%C; 7.28%H; 11.76%N.

EXAMPLE 19N-[1-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)-N'-methylureahydrochloride

A solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11 (3.5 g, 13 mmole) and methyl isocyanate (0.8 g, 14 mmole) in125 ml benzene was stirred at 50° C. for four hours, then was cooled andevaporated to a solid. This material was dissolved in warm isopropanoland converted to the hydrochloride salt as in Example 2. Upon cooling,the product precipitated and was collected to give 3.6 g (76%) of asolid, d 250°-251° C. This material was again recrystallized fromisopropanol to give 3.2 g (68%) ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)-N'-methylureahydrochloride, d 252°-253° C.

ANALYSIS: Calculated for C₁₉ H₂₆ N₄ O.HCl: 62.88%C; 7.50%H; 15.44%N.Found: 62.99%C; 7.55%H; 15.31%N.

EXAMPLE 20

a. 1-[2-(2-Thienyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine

A solution of 1-(2-thienylethyl)-4-piperidone (24.6 g, 0.12 mole) and1-aminopyrrole (12 g, 0.15 mole) in 200 ml of benzene was stirred atreflux for 4 hours. The resultant mixture was cooled and evaporated toan oil which in turn was dissolved in 200 ml of isopropanol and 50 ml ofmethanol. To the resultant solution was added NaBH₄ (9.1 g, 0.24 mole).The mixture was stirred at 80° C. for 2 hours, cooled, evaporated,stirred with water and then extracted with ethyl acetate-ether. Theorganic extract was washed twice with water and saturated NaCl solutionand was dried (anhydrous MgSO₄), filtered and evaporated to 33 g of anoil of 1-[2-(2-thienyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine.

b.N-{1-[2-(2-Thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamidehydrochloride

To a solution of1-[2-(2-thienyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine of Example 20a(5 g, 18 mmole) in 150 ml dichloromethane containing sodium bicarbonate(5 g, 60 mmole) was added a solution of propionyl chloride (2 g, 22mmole) in 20 ml dichloromethane. After stirring two hours at ambienttemperature, the reaction mixture was evaporated, stirred with water andextracted into ethyl acetate-ether. The organic extract was washed withwater and saturated sodium chloride and was dried (anhydrous MgSO₄),filtered and evaporated to give 6.2 g of an oil. This oil was purifiedby HPLC (silica gel, 20% ethyl acetate in dichloromethane) to give 4 g(67%) of an oil. This oil was converted to the hydrochloride salt as inExample 2 and was recrystallized from isopropanol to give 4.3 g (63%) ofN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl) propanamidehydrochloride, d 276°-277° C.

ANALYSIS: Calculated for C₁₈ H₂₅ N₃ OS.HCl: 58.75%C; 7.12%H; 11.42%N.Found: 58.82%C; 7.16%H; 11.17%N.

EXAMPLE 21N-[2-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)cyclobutanecarboxylicacid amide hydrochloride

To a solution of 1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine ofExample 11 (4.4 g, 16 mmole) in 150 ml dichloromethane containing sodiumbicarbonate (5 g, 60 mmole) was added a solution ofcyclobutanecarboxylic acid chloride (2.1 g, 18 mmole) in 25 mldichloromethane. After stirring twenty hours at ambient temperature, thereaction mixture was evaporated, stirred with water and extracted withether. The organic extract was washed with water and saturated sodiumchloride and was dried (anhydrous MgSO₄), filtered and evaporated to 6.5g of a solid. This material was purified by HPLC (silica gel, 25% ethylacetate in dichloromethane) to give 5.2 g (91%) of a solid mp 103°-105°C. This material was converted to the hydrochloride salt as in Example 2in warm isopropanol and, upon cooling, yielded 5.0 g (79%) ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)cyclobutanecarboxylicacid amide hydrochloride, d 264°- 265° C.

ANALYSIS: Calculated for C₂₂ H₂₉ N₃ O.HCl: 68.11%C; 7.79%H; 10.83%N.Found: 68.24%C; 7.68%H; 10.78%N.

EXAMPLE 22 N-{1-[2-(2-Thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamic acid ethyl ester hydrochloride

To a solution of1-[2-(2-thienyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine of Example 20a(5 g, 18 mmole) in 150 ml dichloromethane containing sodium bicarbonate(5 g, 60 mmole) was added a solution of ethyl chloroformate (2.4 g, 22mmole) in 20 ml dichloromethane. After stirring twenty hours at ambienttemperature, the reaction mixture was evaporated, stirred with water andextracted with ethyl acetate-ether. The organic extract was washed withwater and saturated sodium chloride and was dried (anhydrous MgSO₄),filtered and evaporated to give 6.3 g of a solid. This solid waspurified by HPLC (silica gel, 20% ethyl acetate in dichloromethane) togive 4 g (64%) of a solid mp 104°-106° C. This material was converted tothe hydrochloride salt as in Example 2 and was recrystallized fromisopropanol to give 4 g (57%) ofN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol- 1-yl) carbamicacid ethyl ester hydrochloride, d 212°-213° C.

ANALYSIS: Calculated for C₁₈ H₂₅ N₃ O₂ S.HCl: 56.31%C; 6.83%H; 10.95%N.Found: 56.22%C; 6.85%H; 10.86%N.

EXAMPLE 23N-[1-(2-Phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanethioamidehydrochloride

A mixture ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamide ofExample 2 (4.2 g, 13 mmole) and p-methoxyphenylthionophosphine sulfidedimer (2.2 g, 6.5 mmole) in 25 ml dioxane was stirred at 70° C. for twohours then was cooled, stirred with 500 ml water and was extracted withethyl acetate. The organic extract was washed with water and saturatedNaCl and was dried (anhydrous MgSO₄), filtered and evaporated to 6 g ofan oil. This oil was converted to the hydrochloride salt as in Example 2and was recrystallized from isopropanol to give 2.1 g (43%) ofN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanethioamidehydrochloride, d 252°-253° C.

ANALYSIS: Calculated for C₂₀ H₂₇ N₃ S.HCl: 63.55%C; 7.47%H; 11.12%N.Found: 63.65%C; 7.39%H; 11.01%N.

We claim:
 1. A compound having the formula ##STR19## where R ishydrogen, loweralkyl, Arloweralkyl of the formula ##STR20## where Z ishydrogen, loweralkyl, loweralkoxy, halogen, CF₃, NO₂, NH₂ ;cycloalkylloweralkyl, loweralkenyl and thienylloweralkyl; R₁ ishydrogen, loweralkyl, loweralkylcarbonyl, loweralkoxycarbonyl,loweralkylthiocarbonyl, cyano, loweralkylaminocarbonyl,diloweralkylaminocarbonyl, cycloalkylcarbonyl,cycloalkylloweralkylcarbonyl and loweralkenylcarbonyl; R₂ is hydrogen,halogen and --CH₃ ; and the pharmaceutically acceptable addition saltsthereof.
 2. The compound as defined in claim 1 wherein R is ##STR21## 3.The compound as defined in claim 2 wherein R₁ is lower alkoxycarbonyl,loweralkylcarbonyl and cyano.
 4. The compound as defined in claim 3wherein R₂ is hydrogen.
 5. The compound as defined in claim 1 which isN-(₁ -methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide or apharmaceutically acceptable addition salt thereof.
 6. The compound asdefined in claim 1 which isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamide or apharmaceutically acceptable addition salt thereof.
 7. The compound asdefined in claim 1 which isN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)acetamide or apharmaceutically acceptable addition salt thereof.
 8. The compound asdefined in claim 1 which isN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidethyl ester or a pharmaceutically acceptable addition salt thereof. 9.The compound as defined in claim 1 which isN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidmethyl ester or a pharmaceutically acceptable addition salt thereof. 10.The compound as defined in claim 1 which isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) cyanamide or apharmaceutically acceptable addition salt thereof.
 11. The compound asdefined in claim 1 which isN-{1-[2-(4-chlorophenyl)ethyl]-piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamicacid ethyl ester or a pharmaceutically acceptable addition salt thereof.12. The compound as defined in claim 1 which isN-{1-[2-(4-chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable addition salt thereof.
 13. The compoundas defined in claim 1 which isN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acid ethylester or a pharmaceutically acceptable addition salt thereof.
 14. Thecompound as defined in claim 1 which isN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanamide or apharmaceutically acceptable addition salt thereof.
 15. The compound asdefined in claim 1 which is1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine or a pharmaceuticallyacceptable addition salt thereof.
 16. The compound as defined in claim 1which isN-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable addition salt thereof.
 17. The compoundas defined in claim 1 which isN-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)cyanamideor a pharmaceutically acceptable addition salt thereof.
 18. The compoundas defined in claim 1 which is1-(2-phenethyl)-4-[N-(n-propyl)-N-(1H-pyrrol-1-yl)]aminopiperidine or apharmaceutically acceptable addition salt thereof.
 19. The compound asdefined in claim 1 which isN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamide or apharmaceutically acceptable addition salt thereof.
 20. The compound asdefined in claim 1 which isN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidethyl ester or a pharmaceutically acceptable addition salt thereof. 21.The compound as defined in claim 1 which isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamicacid-(n-butyl)ester or a pharmaceutically acceptable addition saltthereof.
 22. The compound as defined in claim 1 which isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) acrylamide or apharmaceutically acceptable addition salt thereof.
 23. The compound asdefined in claim 1 which isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)-N'-methylurea or apharmaceutically acceptable addition salt thereof.
 24. The compound asdefined in claim 1 which isN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable addition salt thereof.
 25. The compoundas defined in claim 1 which isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)cyclobutanecarboxylic acid amide or a pharmaceutically acceptableaddition salt thereof.
 26. The compound as defined in claim 1 which isN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamic acidethyl ester or a pharmaceutically acceptable addition salt thereof. 27.The compound as defined in claim 1 which isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanethioamide ora pharmaceutically acceptable addition salt thereof.
 28. An analgesiccomposition which comprises an effective pain alleviating amount of acompound of the formula ##STR22## where R is hydrogen, loweralkyl,Arloweralkyl of the formula ##STR23## where Z is hydrogen, loweralkyl,loweralkoxy, halogen, CF₃, NO₂, NH₂ ; cycloalkylloweralkyl, loweralkenyland thienylloweralkyl; R₁ is hydrogen, loweralkyl, loweralkylcarbonyl,loweralkoxycarbonyl, loweralkylthiocarbonyl, cyano,loweralkylaminocarbonyl, diloweralkylaminocarbonyl, cycloalkylcarbonyl,cycloalkylloweralkylcarbonyl and loweralkenylcarbonyl; R₂ is hydrogen,halogen and --CH₃ ; and the pharmaceutically acceptable addition saltsthereof.
 29. The composition as defined in claim 28 wherein R is##STR24##
 30. The composition as defined in claim 29 wherein R₁ is loweralkoxycarbonyl, loweralkylcarbonyl and cyano.
 31. The composition asdefined in claim 30 wherein R₂ is hydrogen.
 32. The composition asdefined in claim 28 which comprisesN-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide or apharmaceutically acceptable salt thereof.
 33. The composition as definedin claim 28 which comprisesN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamide or apharmaceutically acceptable salt thereof.
 34. The composition as definedin claim 28 which comprisesN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)acetamide or apharmaceutically acceptable salt thereof.
 35. The composition as definedin claim 28 which comprisesN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidethyl ester or a pharmaceutically acceptable salt thereof.
 36. Thecomposition as defined in claim 28 which comprisesN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidmethyl ester or a pharmaceutically acceptable salt thereof.
 37. Thecomposition as defined in claim 28 which comprisesN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) cyanamide or apharmaceutically acceptable salt thereof.
 38. The composition as definedin claim 28 which comprisesN-{1-[2-(4-chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamicacid ethyl ester or a pharmaceutically acceptable salt thereof.
 39. Thecomposition as defined in claim 28 which comprisesN-{1-[2-(4-chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable salt thereof.
 40. The composition asdefined in claim 28 which comprisesN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acid ethylester or a pharmaceutically acceptable salt thereof.
 41. The compositionas defined in claim 28 which comprisesN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanamide or apharmaceutically acceptable salt thereof.
 42. The composition as definedin claim 28 which comprises1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine or a pharmaceuticallyacceptable salt thereof.
 43. The composition as defined in claim 28which comprisesN-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable salt thereof.
 44. The composition asdefined in claim 28 which comprisesN-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)cyanamideor a pharmaceutically acceptable salt thereof.
 45. The composition asdefined in claim 28 which comprises1-(2-phenethyl)-4-[N-(n-propyl)-N-(1H-pyrrol-1-yl)]aminopiperidine or apharmaceutically acceptable salt thereof.
 46. The composition as definedin claim 28 which comprisesN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanamide or apharmaceutically acceptable salt thereof.
 47. The composition as definedin claim 28 which comprisesN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidethyl ester or a pharmaceutically acceptable salt thereof.
 48. Thecomposition as defined in claim 28 which comprisesN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamicacid-(n-butyl)ester or a pharmaceutically acceptable salt thereof. 49.The composition as defined in claim 28 which comprisesN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) acrylamide or apharmaceutically acceptable salt thereof.
 50. The composition as definedin claim 28 which comprisesN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)-N'-methylurea or apharmaceutically acceptable salt thereof.
 51. The composition as definedin claim 28 which comprisesN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable salt thereof.
 52. The composition asdefined in claim 28 which comprisesN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)cyclobutanecarboxylic acid amide or a pharmaceutically acceptable saltthereof.
 53. The composition as defined in claim 28 which comprisesN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamic acidethyl ester or a pharmaceutically acceptable salt thereof.
 54. Thecomposition as defined in claim 28 which comprisesN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanethioamide ora pharmaceutically acceptable salt thereof.
 55. A method of alleviatingpain in a mammal which comprises administering to a mammal in needthereof an effective pain relieving amount of a compound having theformula ##STR25## where R is hydrogen, loweralkyl, Arloweralkyl of theformula ##STR26## where Z is hydrogen, loweralkyl, loweralkoxy, halogen,CF₃, NO₂, NH₂ ; cycloalkylloweralkyl, loweralkenyl andthienylloweralkyl; R₁ is hydrogen, loweralkyl, loweralkylcarbonyl,loweralkoxycarbonyl, loweralkylthiocarbonyl, cyano,loweralkylaminocarbonyl, diloweralkylaminocarbonyl, cycloalkylcarbonyl,cycloalkylloweralkylcarbonyl and loweralkenylcarbonyl; R₂ is hydrogen,halogen and --CH₃ ; and the pharmaceutically acceptable addition saltsthereof.
 56. The method as defined in claim 55 wherein R is ##STR27##57. The method as defined in claim 56 wherein R₁ is loweralkoxycarbonyl,loweralkylcarbonyl and cyano.
 58. The method as defined in claim 57wherein R₂ is hydrogen.
 59. The method as defined in claim 55 whereinsaid compound isN-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide or apharmaceutically acceptable salt thereof.
 60. The method as defined inclaim 55 wherein said compound isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)propanamide or apharmaceutically acceptable salt thereof.
 61. The method as defined inclaim 55 wherein said compound isN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)acetamide or apharmaceutically acceptable salt thereof.
 62. The method as defined inclaim 55 wherein said compound isN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidethyl ester or a pharmaceutically acceptable salt thereof.
 63. Themethod as defined in claim 55 wherein said compound isN-[1-(2-phenylethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidmethyl ester or a pharmaceutically acceptable salt thereof.
 64. Themethod as defined in claim 55 wherein said compound isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) cyanamide or apharmaceutically acceptable salt thereof.
 65. The method as defined inclaim 55 wherein said compound isN-{1-[2-(4-chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamicacid ethyl ester or a pharmaceutically acceptable salt thereof.
 66. Themethod as defined in claim 55 wherein said compound isN-{1-[2-(4-chlorophenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable salt thereof.
 67. The method as definedin claim 55 wherein said compound isN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)carbamic acid ethylester or a pharmaceutically acceptable salt thereof.
 68. The method asdefined in claim 55 wherein said compound isN-[1-(n-butyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanamide or apharmaceutically acceptable salt thereof.
 69. The method as defined inclaim 55 wherein said compound is1-(2-phenethyl)-4-(1H-pyrrol-1-yl)aminopiperidine or a pharmaceuticallyacceptable salt thereof.
 70. The method as defined in claim 55 whereinsaid compound isN-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable salt thereof.
 71. The method as definedin claim 55 wherein said compound isN-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)cyanamideor a pharmaceutically acceptable salt thereof.
 72. The method as definedin claim 55 wherein said compound is1-(2-phenethyl)-4-[N-(n-propyl)-N-(1H-pyrrol-1-yl)]aminopiperidine or apharmaceutically acceptable salt thereof.
 73. The method as defined inclaim 55 wherein said compound isN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanamide or apharmaceutically acceptable salt thereof.
 74. The method as defined inclaim 55 wherein said compound isN-[1-(2-phenylpropyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamic acidethyl ester or a pharmaceutically acceptable salt thereof.
 75. Themethod as defined in claim 55 wherein said compound isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) carbamicacid-(n-butyl)ester or a pharmaceutically acceptable salt thereof. 76.The method as defined in claim 55 wherein said compound isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) acrylamide or apharmaceutically acceptable salt thereof.
 77. The method as defined inclaim 55 wherein said compound isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)-N'-methylurea or apharmaceutically acceptable salt thereof.
 78. The method as defined inclaim 55 wherein said compound isN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)propanamideor a pharmaceutically acceptable salt thereof.
 79. The method as definedin claim 55 wherein said compound isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl)cyclobutanecarboxylic acid amide or a pharmaceutically acceptable saltthereof.
 80. The method as defined in claim 55 wherein said compound isN-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)carbamic acidethyl ester or a pharmaceutically acceptable salt thereof.
 81. Themethod as defined in claim 55 wherein said compound isN-[1-(2-phenethyl)piperidin-4-yl]-N-(1H-pyrrol-1-yl) propanethioamide ora pharmaceutically acceptable salt thereof.
 82. A method of forming acompound having the formula ##STR28## where R is hydrogen, loweralkyl,Arloweralkyl of the formula ##STR29## where Z is hydrogen, loweralkyl,loweralkoxy, halogen, CF₃, NO₂, NH₂, cycloalkylloweralkyl, loweralkenyland thienylloweralkyl; R₁ is hydrogen, loweralkyl, loweralkylcarbonyl,loweralkoxycarbonyl, loweralkylthiocarbonyl, cyano,loweralkylaminocarbonyl, diloweralkylaminocarbonyl, cycloalkylcarbonyl,cycloalkylloweralkylcarbonyl and loweralkenylcarbonyl; R₂ is hydrogen,halogen and --CH₃ ; and the pharmaceutically acceptable addition saltsthereof, which comprises: reacting a first compound of the formula##STR30## where R and R₂ are as previously defined with a secondcompound selected from ##STR31## where Hal is a halogen, R₃ is (C₁-C₅)alkyl, a (C₁ -C₅)alkenyl and cycloalkyl, R₄ is a (C₁ -C₆)alkyl andR₅ is a (C₁ -C₆)alkyl.
 83. The method as defined in claim 82 whereinsaid second compound is ##STR32## and which further comprises reducingthe carbonyl of the resultant product to form a compound having theformula ##STR33##
 84. The method as defined in claim 82 wherein saidsecond compound is ##STR34## and which further comprises reacting theresultant reaction product with p-methoxyphenylthionophosphine sulfidedimer to form a compound having the formula ##STR35##
 85. The method asdefined in claim 82 wherein said second compound is R₅ --N═C═O and whichfurther comprises alkylating the resultant reaction product to form acompound having the formula ##STR36##